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PLoS One. 2022; 17(4): e0266462. PMCID: PMC9000089

Published online 2022 Apr 11. doi: 10.1371/journal.pone.0266462 PMID: 35404955

Blockchain technology in healthcare: A systematic review

Huma Saeed, Data curation, Methodology, Writing – original draft, 1 Hassaan Malik, Conceptualization, Data curation, Supervision, Writing – original draft, 1 , 2 ,*
Umair Bashir, Conceptualization, Formal analysis,
Writing – review & editing, 1 Aiesha Ahmad, Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, 1 Shafia Riaz, Data curation, Funding acquisition, Methodology, 1
Maheen Ilyas, Conceptualization, Formal analysis, Methodology, Writing – original draft, 1 Wajahat Anwaar Bukhari, Data curation, Formal analysis, Writing – review & editing, 1 and Muhammad Imran Ali Khan,
Conceptualization, Data curation, Resources 1

Pandi Vijayakumar, Editor

Abstract

Blockchain technology (BCT) has emerged in the last decade and added a lot of interest in the healthcare sector. The purpose of this systematic literature review (SLR) is to
explore the potential paradigm shift in healthcare utilizing BCT. The study is compiled by reviewing research articles published in nine well-reputed venues such as IEEE
Xplore, ACM Digital Library, Springs Link, Scopus, Taylor & Francis, Science Direct, PsycINFO, Ovid Medline, and MDPI between January 2016 to August 2021. A total of 1,192
research studies were identified out of which 51 articles were selected based on inclusion criteria for this SLR that presents the modern information on the recent implica‐
tions and gaps in the use of BCT for enhancing the healthcare procedures. According to the outcomes, BCT is being applied to design the novel and advanced interventions to
enrich the current protocol of managing, distributing, and processing clinical records and personal medical information. BCT is enduring the conceptual development in the
healthcare domain, where it has summed up the substantial elements through better and enhanced efficiency, technological innovation, access control, data privacy, and secu‐
rity. A framework is developed to address the probable field where future researchers can add considerable value, such as data protection, system architecture, and regula‐
tory compliance. Finally, this SLR concludes that the upcoming research can support the pervasive implementation of BCT to address the critical dilemmas related to health
diagnostics, enhancing the patient healthcare process in remote monitoring or emergencies, data integrity, and avoiding fraud.

Introduction

Healthcare is a system that includes 3 main components: (i) Main suppliers of services for medical treatment, For instance, doctors, nurses, technicians, and hospital adminis‐
trations (ii) Emergency related services [1–4], and (iii) Health and health-oriented service users, specific patients. In the current study, to encourage, preserve or restore the
health of beneficiaries, we examine the health maintenance to include technology-based remotely controlling services increased by constituent service providers [5–9]. In the
medical field, every year, there are more security and privacy breaches, in 2017, more than 300 breaches were reported, and up to 37 million records were affected during
2010–2017 [10, 11]. The growing digitization of medical care has advanced the acknowledgment of issues about secure storage, accessing of patients’ medical records, own‐
ership, and medical data from associated sources [12–16]. Blockchain is recommended as a method of addressing critical issues faced by healthcare, for instance, protected
sharing of health records and adherence to data privacy laws [17–19].

Blockchain is a particular type of database that can be managed by the network of authenticated members or nodes [13] and stores immutable information blocks that can
be strongly exchanged without interference by third parties [10]. With cryptographic signatures and the use of consensus algorithms which are implemented as key enablers
in their application, data is stored and registered [20]. The capability of preserving data is a major aim for using the BCT particularly in healthcare [21], which is subject to
massive sharing and dissemination of a significant amount of data [7]. In different stages, the development of blockchain technology, as well as its application in various con‐
texts, had been materialized. The first phase of blockchain development was focused on cryptocurrencies, while the second focused on the use of smart contracts in indus‐
tries like real estate and finance [11, 22]. The 3rd generation of evolution concentrated on employing blockchain in non-financial areas including government, culture [23],
and healthcare space [22, 24]. Also, powered by revolutionary technical features such as data immutability [25], with the introduction of artificial intelligence, blockchain
technology is having its 4th generation of evolution [26]. This asserted diversity in Blockchain’s application spectrum can be attributed to its ability to build decentralized [27]
and trustless transaction environments [28]. As blockchain can tackle serious issues, such as automated claim authentication [9] and public health management [29], the
healthcare sector is a prime choice for the application of blockchain technology [30–32]. This technology allows patients to keep personal data and determine with whom this
can be shared, thus resolving current data ownership, and sharing issues [28, 33]. At the same time, it allows recorded data to be integrated, modified, shared safely, and re‐
trieved on time by relevant authorities using consensus protocols [31]. This is a significant benefit of the use of this technology in the healthcare system, as existing proce‐
dures need third parties to store the data [10]. Finally, because of possible human error, blockchain could potentially add accountability to data management processes [34]
further decreasing the risks of mishandling or misusing recorded data [31]. Given the optimistic connotations of the effects of blockchain on social and business change, in
contrast to previously defined expectations, it appears to be a discussion regarding its basic and derived advantages. A recent study indicates that while organizations will
make substantial investments in the future in adopting blockchain-based technology due to a widespread perception that the advantages could be over-hype, they will proba‐
bly accept a cautiously pragmatic approach [35]. It can be said that this technology has yet to fulfill its expectations [36], a fact that can be due to the prevalent adoption of
block chain, particularly about regulatory barriers, to certain challenges [31]. The general public and specific users, for instance, patients or physicians are not acquainted
with the way blockchain works, the technological features, or its advantages for data processing is another significant obstacle in promulgating the implementation of
blockchain [35]. Suggest that it may take a considerable time for this technology to establish all anticipated stages of business transformation mainly because of the organiza‐
tional, social, and implementation challenges, for example, security issues or governance reasons [22, 31]. This could also be exacerbated by general confusion regarding the
use of blockchain regarding legal enforcement and regulations of the government. Current research focuses on supporting blockchain operational growth and speed-up its
prevalence by overcoming these barriers.

However, previous studies have made little attempt to comprehensively summarize the existing knowledge by using SLRs [9–13]. For example, bibliometric techniques were
used by [10] to provide a summary of blockchain research patterns and components related to the implementation of blockchain in the field of healthcare. In [9] the different
blockchain platforms have been developed to deploy blockchain in healthcare. The study [11] addressed different examples of the implementation in the healthcare of
blockchain technology, the problems, and their potential solutions. In diverse contexts where this technology was implemented [12], addressed design choices and tradeoffs
made by the researchers. The research studies of [13, 14] have discussed the Blockchain-based applications throughout numerous industries and addressed many contexts
of use for this technology in a broad manner. Recently [14] reviewed 39 studies to present an overview on common channels and other areas where blockchain technology is
utilized for healthcare enhancement. Although these systematic literature reviews have a contribution to the extent of knowledge, their emphasis has been mainly on synthe‐
sizing or delineating blockchain technology patterns and areas [10, 11, 13, 14, 16]. However, researchers will get benefit from a concentrated discussion on the implications
of its adoption [15], along with concrete obstacles and areas for progress for advancing the field, due to the reach and diversity of previous blockchain studies [11]. Through
assimilating existing information and describing focus areas that require considerable academic attention, review-based research will assist in meeting these needs [11, 16–
19]. As a result of this necessity, we perform an SLR on the blockchain technology application. This SLR presents a valuable overview of ongoing research, gaps in current
knowledge, and future avenues of research as well. The contribution of this study is in two ways, this research adds to the emerging blockchain literature in healthcare. First
regarding their implementation areas, restrictions, and recommendations, it offers an advanced and thematically ordered classification of previous literature. Second, we pro‐
pose a synthesizing process according to the results of the SLR to detail possible topics that need academic attention to further update the existing body of literature.

The present study is organized as follows: In Section 2, we provide a thorough description of the research method utilized to search, screen, and select the literature. In
Section 3, we present relevant review works that have been conducted in the field of health care using blockchain technology and discuss all the papers that have been se‐
lected, focusing on their main findings, and highlighting research gaps for future research. Finally, in Section 4we conclude this study.

Methodology

SLRs always provide a thorough understanding of literature as it presents a complete and systematized review meeting all standard protocols in it [18, 37–39]. SLRs also help
in the understanding of current information gaps and, as a result, the discovery of potential research avenues [19].

Research questions

We conduct this SLR by addressing the following research questions (RQs).

RQ1: What is the advanced profile used for the employment of blockchain in the healthcare domain?

The purpose of this research question is to identify the number of research papers issued every year, the average citation received on research papers yearly, and aca‐
demic contribution on the subject by Journals, publishing houses, and community.

RQ2: What are the major healthcare domains where blockchain technology has been implemented?

The purpose of this question is to identify the contexts in which blockchain technology has shown significant outcomes in healthcare.

RQ3: What are the existing problems and constraints raised by the previous studies in the healthcare field using blockchain technology?

The motivation behind this question is to identify existing problems and issues of blockchain technology in the healthcare field based on results, limitations, and conclu‐
sions of previous research studies.

RQ4: What are the potential healthcare avenues that would benefit from blockchain technology implementation?

The purpose of this question is to identify growing gaps and prospects of the future research agenda

Research objectives

The research objectives (ROs) of the article herein presented are the following:

RO1: Establishing an archive of work that relates a wide topic about Blockchain in healthcare and offers an open dataset about Blockchain for all other researchers.
RO2: Identify a more focused set of studies that have used blockchain technology in healthcare applications.
RO3: Identify problems and constraints discussed in the healthcare field using blockchain technology.
RO4: Characterize existing solutions in the field of blockchain in healthcare and clarify the similarities and differences between them using a characterization framework.
Research strategy

Nine databases—IEEE Xplore, ACM Digital Library, Springs Link, Scopus, Taylor & Francis, Science Direct, PsycINFO, Ovid Medline, MDPI—are recognized by previous studies
as standard data sources of research papers about health informatics [40]. Reviewed papers have been outlined for understanding the research status of applying
blockchain in health care. For the right database search the three keyword combinations existed as—“blockchain and Healthcare”, or “medical Health” or Medical
Management or Health Management. The above keywords were extracted from an article of previous literature i.e. SLRs) using similar keywords such as blockchain and med‐
ical healthcare.

Study selection

The selection process aimed to find the articles that are the most relevant to the objective of this SLR. If there was the same paper in more than one source, as per our re‐
search, it was considered only once. The content of the papers chosen for the final sample was evaluated [39, 41] to make sure that the findings of the present SLR produced
clear results and that is not biased. For reaching a consensus of final inclusion or exclusion, two of the researchers finalized the evaluation. After completing this, the discrep‐
ancies of individual assessments were addressed through discussion. A third author was engaged in analysis and debate in situations where the two writers did not find con‐
sensus. After the papers were found, the first move was to delete redundant titles and those which are not connected in scrutiny. The standards for inclusion were limited to
the hunt for String, and a study conducted by at least one of the following criteria for exclusion (EC) is omitted:

Inclusion criteria (IC`s)

IC1: Studies are released any time on or before August 2021.

IC2: Studies are limited to the journal, conference, report, workshop, and symposium articles only.
IC3: Availability of complete texts in digital databases.
IC4: Proposed models or frameworks present.

Exclusion criteria (EC)

EC1: Exclude duplicated studies.

EC2: Eliminate preview, book chapters, magazines, thesis, monographs, and interview-based articles.
EC3: Exclude studies based on quality evaluation criteria.
EC4: Studies written in a language other than English.

The choice of papers was based on clear above discussed criteria for inclusion and exclusion. Below Fig 1 has been developed through the aspiration from the PRISMA dia‐
gram [42]. Fig 1 shows the study selection process.
 Fig 1

PRISMA flow chart-based studies selection process.

Results and discussion

This section describes the outcomes related to the systematic study RQs discussed above. 51 research studies have been selected to illustrate the outcomes of each RQs.
Publication and other selection biases are a potential threat to validity in all SLR and we cannot exclude the possibility that some research studies were missed resulting in re‐
duced precision and the potential for bias. Therefore, we made significant efforts in finding all eligible research articles, and conference proceedings from different well-re‐
puted databases and by contacting experts in the BCT area through social media platforms. We believe that our work provides a significant contribution to the role of
blockchain technology in health care.

Selection results

Our search identified 1177 records, of which 1126 were screened as shown in Fig 1. 51 research articles were included in this SLR. The list of selected papers with descrip‐
tions of the overall classification results are discussed below.

RQ1: What is the advanced profile used for the employment of blockchain in the healthcare domain? This SLR addresses the achieved descriptive records about the number of
articles that have been published each year, publication source, the average citation received on research papers yearly (see Table 1). To complete this SLR, we have examined
published surveys, systematic literature review (SLR), systematic reviews (SR), and research papers related to blockchain in healthcare, and published in the field of
blockchain from 2018 to 2021. The number of highest citation research articles with the most citations is shown in Table 1.
 Table 1

List of the selected papers with details of QE, publication channel, year, H-index, and citation per year.

[47] 52 Journal of Intelligent & Fuzzy Systems - 38 21 2 61

[48] 43 Sustainable cities and society 19 67 112 15 242

[49] 76 Business Process Management Journal - 1 7 2 10

[50] 153 Sensors - 52 119 21 211

[51] 67 IEEE Internet of Things Journal - 10 13 1 26

[52] 70 Journal of medical systems 4 14 10 - 30

[53] 70 Journal of medical systems 10 69 135 13 245

[54] 86 IEEE access 21 74 85 14 227

[55] 44 Cognitive Systems Research 15 28 42 6 89

[56] 20 Future Internet - 2 6 2 12

[57] 105 Future Generation Computer Systems - 3 18 5 31

[58] 16 Electronics - 3 38 11 57

[59] 70 Journal of medical systems 3 23 56 1 92

[60] 93 International Journal of Distributed Sensor Networks 1 7 11 1 10

[61] 17 applied sciences - 1 8 1 10

[62] 70 Journal of medical systems 4 35 42 9 103

[63] 86 IEEE Access - 5 18 3 28

[64] 108 Oncotarget 18 56 57 11 154

[65] 68 The Journal of Behavioral Health Services & Research 1 2 28 2 37

[66] 86 IEEE access - 9 49 4 74

[67] 105 Future generation computer systems 1 17 56 8 88

[68] 60 Wireless Communications and Mobile Computing - 1 4 1 8

[69] 17 Applied sciences 1 6 39 11 62

[70] 70 Journal of medical systems - 11 14 3 32

[71] 86 IEEE Access 1 23 39 14 83

[72] 70 Applied Innovation 2 34 46 8 103

[73] 298 Nature communications 1 11 32 4 49

[74] 17 Applied Sciences - 7 14 2 22

[75] 70 Journal of medical systems 5 41 59 12 136

[28] 37 Computational and structural biotechnology journal 10 78 120 9 237

[76] 127 Journal of medical Internet research - 3 25 2 31

[77] 70 Journal of medical systems 5 21 26 4 57

[15] 99 International Journal of Medical Informatics - - 29 9 46

[78] 93 Computers in Industry - - 7 6 13

[79] 86 IEEE Access - - 12 4 16

[80] 153 Sensors - - 13 3 17

[31] 89 IEEE Transactions on Engineering Management. - - 4 2 6

[81] N/A International Journal of Environmental Research and Public Health - - - 4 4

[82] N/A International Journal of Healthcare Information Systems and Informatics - - 1 2 3

[83] 86 IEEE Access - - 6 3 10

[84] - Electronics - - 27 8 38

[71] 86 IEEE Access 1 23 42 12 83

Fig 2 demonstrates the number of articles published each year from 2018–2021. The four obvious outliers are existing from 2018 to 2021. In 2018, 24 articles were pub‐
lished, 16 articles were published in 2019, 9 articles were published in 2020 and 2 articles were published in 2021.
 Fig 2

Number of articles published per year.

The authors of the reviewed articles were found to be affiliated with institutes located across 17 countries. Five countries, China (number of articles = 12), USA (number of
articles = 6), South Korea (number of articles = 4), Brazil (number of articles = 3) and India (number of articles = 3), cumulatively represented 65% of the sample (see Fig 3).

Fig 3

Country-wise publications of selected research studies.

In addition, the analysis of author indexed keywords conducted by using word cloud showed that the main emphasis of article related to “blockchain”, “technology”, “data”,
“healthcare”, “sharing”, and “medical” which are graphically illustrated in Fig 4.
 Fig 4

Constructs key framework.

RQ2: What are the major healthcare domains where blockchain technology has been implemented? In this part, we will discuss a review of the fundamental principles of
blockchain. BCT is used in medicine, especially in managing the information in healthcare that particularly is important in the healthcare area as this technology involves the
sensitive data of patients. This sector is important to society because innovations in this field will enhance the quality of people’s life. Following this logic, the computation can
help to mitigate the effects of certain problems in this field. Informatics, for example, helps in the automation of medical records by ensuring more reliable data sharing, log
management, and other applications. One of the first and most popular blockchain applications in healthcare is the exchange of health records. Information related to health
is difficult to disclose because it is labeled as confidential information and includes patients’ details. Among the key works in the literature that discuss this application of
blockchain technology are: [85, 86]. The characteristics of blockchain-based architectures for the sharing of electronic healthcare records can vary. The features of
blockchain-based systems for the exchange of electronic healthcare records may vary. One of the most well-known structures in the literature is discussed in the work of
Azaria et al. [86]. Several recent papers in the literature have cited this as a framework for the development of other similar architectures. Some of these systems are inspired
by Azaria et al. [86] cited in [30, 79, 87, 88]. Voting is a formal statement of an individual’s or a group’s opinion or choice, whether positive or negative. Traditional voting
methods, on the other hand, are centralized and are known to have security and efficiency flaws. The study [89] examines blockchain-based voting systems in depth and cate‐
gorizes them based on a variety of characteristics e.g., the types of blockchain used, the consensus approaches used, and the scale of participants. Artificial intelligence (AI) is
now the core technology for a wide range of applications, from self-driving cars to smart cities. One of the most crucial pillars of social and economic stability is smart health‐
care, which is an integral part of smart cities. The research study [90] focused on designing a human-in-the-loop-aided (HitL-aided) scheme to protect patient privacy in
smart healthcare. Profile matching technology can facilitate the sharing of medical information across patients by matching similar symptom traits. However, because the
symptom attributes are linked to sensitive information about patients, their privacy will be compromised during the IoMT matching process. To accomplish fine-grained pro‐
file matching, the study [91] provides a verifiable private set intersection scheme and used a re-encryption technique to preserve patients’ privacy. Technologically advanced
countries are exploring or implementing smart homes, it is convenient but risky. Most of the existing solutions are generally based on a single-server architecture, which has
limitations in terms of privacy, integrity, and confidentiality. While blockchain-based solutions may alleviate some of these problems, they still face some significant obstacles.
Lin et al. [92] developed a revolutionary safe mutual authentication method for use in smart homes and other applications. MedRec will be the first sharing architecture to be
discussed, which uses a blockchain-based system to store electronic medical records. The MedRec considers resolving issues as data access response time, interoperability,
and increased data quality in healthcare research [86]. It is worth looking into the resources that were used to create MedRec’s architecture, since it implements a private
P2P network (Permission block chain), as well as using Ethereum’s smart contract platform, to make it easier to monitor and track network state transitions. One of the
MedRec architecture’s hallmarks is that it provides patients with a consulting agency that has records of their healthcare background, enabling them to remain informed
about health decisions. Another difference is that they enable the standardization of health data since they are adaptable and provide open data standards in a variety of for‐
mats. This architecture takes a novel approach to the use of health data management systems by enhancing security and establishing a common language for data exchange
for research purposes [86]. While Azaria et al. [86] also plan to perform experiments and analyses with a diverse community of users. In summary, MedRec is a realistic
choice for exchanging healthcare information that can be used to combine patient care, hospital care, and physician care. As a consequence, the reported data can help to
minimize discrepancies among different systems of hospitals. As stated by [85], the method introduces the topic of cloud computing, which could help in creating new archi‐
tectures for sharing healthcare records via blockchain, resulting in safer and more secure healthcare systems for clinical use. The authors propose a cloud-based architecture
that uses a blockchain-based data system to connect a network of communication nodes. The paper [85] shows how to handle the exchange of healthcare information using a
blockchain architecture, which employs the principles of intelligent contracts and, immutable bookkeeping. The major roles of BCT in sharing health information, remote care
with IoT, security, and privacy, and supply chain are depicted in Fig 5.
 Fig 5

Major healthcare domains where BCT has been used.

The list of blockchain-based healthcare methods is discussed in Table 2.

Table 2

Blockchain-based healthcare methods.

Ref Domain Methods

[86] Sharing Health Information MedRec

[93] Sharing Health Information MedRec

[94] Sharing Health Information Medicalchain

[71] Remote Care with IoT Patient-Centric agent (PCA)

[95] Supply Chain for healthcare Modum

[96] Security and Privacy Decentralized sharing of health records (DSHR)

RQ3: What are the existing problems and constraints raised by the previous studies in the healthcare field using blockchain technology? Even though blockchain is a multidisci‐
plinary concept with challenges and limitations, it can be applied to a variety of areas [88]. Researchers in this field are working to overcome or mitigate the negative effects
of these factors. The following are some of the problems (i.e. technological challenges) that blockchain technology faces when used in healthcare [22, 88, 97, 98].

1) Throughput If the number of transactions and nodes in the network grows, more checks will need to be performed, possibly causing a network bottleneck. When dealing
with healthcare systems, high throughput is a challenge because unless there is fast access, it might adversely affect a diagnosis which could save someone’s life [64], corre‐
spondingly recognizing that the suggested framework focuses on identifying inconsistencies will possibly not perform well when datasets are unlabeled. Issues including
specifications for continuous updates by the used system [59], keyword set size [75], network set-up and disk space needed based on the blockchain type, such as Ethereum
software, employed to the framework can all affect a framework’s scalability and performance quality [25, 99]. Similarly [48], suggests that integrating certain features into
established systems, e.g. making global smart deals, can offset higher performance-related costs. Furthermore, a small number of studies have suggested that performance-
related problems can be connected to the node management in a suggested system.

2) Latency Validating a block takes about 10 minutes; this can be harmful to system security services since successful attacks may occur during that time. Healthcare net‐
works are complex and should be accessed at all times, as any delay may negatively affect the analysis of an exam.
3) Security When a party has control of 51 percent of the voting power, this can adversely affect the computing power of the network. This is a serious issue that needs to be
addressed because a harmed healthcare system will lead to healthcare organizations losing their reputation.

4) Resource Consumption Since the mining process consumes a lot of energy, using this technology could result in a significant loss of resources. Since multiple devices are
required to track patients in a healthcare setting, energy costs are high; however, the use of blockchain may result in high computing and energy costs. Managing these ex‐
penses is a challenge for businesses.

5) Usability Since these systems are so complicated, usability is a challenge as well to deal with. Additionally, an API must be developed (Application Programming Interface)
Users would enjoy the user-friendly features. Since not all health practitioners have the same level of education, As IT professionals, we should be able to use frameworks
that are easy and effective.

6) Centralization Even though blockchain has a decentralized design, certain implementations tend to concentrate the miner, which decreases network stability. Because this
central node is insecure and may be hacked, hostile attackers can get access to the data it holds [25].

7) Privacy It is common to suppose that the Bitcoin framework allows blockchain to make sure the privacy of its nodes. The results of [25], on the other hand, contradict this
assumption. Furthermore, strategies to provide this functionality to blockchain-based systems are needed [25]. Due to privacy laws and regulations, blockchain-based sys‐
tems have to conform to the General Data Protection Regulation (GDPR). Our research also indicates those users’ reservations about the safe and ethical utilization of data
could be a major barrier to blockchain adoption in healthcare systems. The existing issues are primarily associated with blockchain technology’s technological limitations,
such as the protection of individual nodes [53], the degree of safety permitted through cryptographic elements implemented with the system [70], besides the preservation
of confidential data whereas requesters complete their computations [100]. However, certain research has drawn attention to more socially relevant issues regarding sharing
of public data [73] and users’ confidence in governments [49, 74]. Such issues may also be linked to the suggested framework protection from the perspective of users for
example users’ management and misuse of permitted personal keys/codes [46].

8) Constraint Prior studies have identified constraints, which can be divided into four categories. These dimensions mean that such constraints extend beyond technical
boundaries (costs of designing, implementing blockchain systems, data analysis for system assessment, and framework constituent elements) to include certain social facets
also such as trust in the administration, infrastructure of technology in a country.

9) Costs This set of constraints is specifically concerned with the time, capital, and economic expenses of putting a system of blockchain into action. For example [50], discuss
resource constraints in IoT, while [28] discuss the costs of arranging dispersed app in the deployment of blockchain. Additional expenses that have been established as con‐
straints and limitations in previous research include the linear increase in protocol costs based on the characteristics and attributes of the entities involved, such as patients
[54], increased operational overhead for the patient, and access latency for the requester [69], the exchange and implementation costs depend upon inconstant inputs in size
and length of a string [67]. The issues related to time are further listed as one of the limitations, i.e. the spent time in finding smart contracts globally [48], increased time con‐
sumption [57], transmission timing [53], the time needed for the data receiver to seek the required data in shared storage [68], and higher overall execution time [21].

RQ4: What are the potential healthcare avenues that would benefit from blockchain technology implementation? Blockchain consists of a sequence of blocks connected with
cryptographic techniques. The immutability of this is one of the most attractive characteristics to many industries. The data that is added to the blockchain is irreversible, con‐
sequently, allowing for the creation of a consensus-based, verifiable, and accurate data ledger. That creates blockchain especially well-suited to tasks wherever integrity of
data is critical; ProvChain [101], an infrastructure based on this technology in giving chain-of-custody to the database, is a functional example of this immutability. There are
many blockchain implementations, including Bitcoin, a cryptocurrency token based on the blockchain; and Ethereum, a cryptocurrency token based on blockchain. Ethereum
[102], a blockchain ledger with Turing-complete computer-generated device that allows smart contracts to implement code on this; and JP Morgan’s Juno [103], an Ethereum
fork that uses the particular consensus mechanism called Quorum, along with several other blockchain implementations. The execution of blockchain varies due to ways in
their consensus approaches. Bitcoin, for example, employs the HashCash [104] Proof-Of-Work algorithm, which is a deliberately slow system intended to avoid denial-of-ser‐
vice attacks. As a vote against the blockchain’s agreement, every Bitcoin miner authenticates this blockchain system by conducting that algorithm. Ethereum includes Ethash,
which is an algorithm called Proof-of-work based on the Dagger-Hashimoto algorithm, as described in the Ethereum Yellow Paper [103]. However, shortly Ethereum is likely
to advance in an algorithm named Casper. It will consider the excess requirement of energy in Proof-of-work [105]. The implementation of smart contracts separates
Ethereum from Bitcoin. The smart contract is one of the snippets of code that run on each blockchain node. These are self-executing contracts in which all members of the
blockchain are bound by the agreement. In the same way, as a standard contract does, they influence advantages, responsibilities, also punishments related to contract-re‐
lated conduct. It could be utilized to model the HIPAA healthcare personal health information (PHI) workflow to satisfy audit and regulatory standards, likewise, done inside
Patientory since they resemble conventional paper contracts and rules [106]. A new type of blockchain trust model, trust in the consortium, is also emerging. Microsoft re‐
cently released the Coco framework, which enables the creation of blockchain-agnostic consortiums [107]. Above mentioned models are based on a pre-defined group of
trustworthy parties. It can be among various clinics or in the UK, NHS Trusts, third parties, and manufacturers of devices. By implementing smart contracts only on the hard‐
ware of trusted partners, without requiring miners, a consensus can be generated. It turned out in remarkably improved results, through a Coco-optimized blockchain case
capable of processing 1600 transactions in a second, taking the blockchain system very close to the major payment processors. Coco also supports a variety of trusted execu‐
tion environments, including Windows Virtual Secure Mode, Arm Trust Zone, and Intel Guard Extensions to name a few.

1) Clinical trials Managing trial subject consent and clinical trials itself is an area in which blockchain can potentially improve the accountability, audit ability, and transparency
of researchers and practitioners in the medical field. By keeping the unchangeable log of a patient’s approval, officials could control the standard of clinical trials easily, mak‐
ing sure it complies with informed consent regulations of the country. It is especially important because a forged informed consent form is one of the common types of clini‐
cal fraud. It involves falsifying patient consent and editing records, implying that authentication of trial subjects is essential for avoiding it. That kind of setup may be improved
by implementing a smart contract system that stops clinicians to use the data of patients unless a key is issued by the end of an auditable process of smart contract that re‐
quires permission in each step in the trial, as proposed by Benchoufi, Porcher, and Ravaud. This procedure should also allow the patient’s consent to be revoked. Executing
the clinical trial of blockchain consent log provides the subjects with data ownership while also having a trail of audit for regulators, medical professionals, and researchers.
The role of BCT in clinical trials is graphically represented in Fig 6.
 Fig 6

Role of blockchain in clinical trials.

2) Sharing the data Sharing information is regarded as the most significant opportunity for improvement in healthcare; however, it too poses a significant challenge in pri‐
vacy. Sharing the data using BCT is presented in Fig 7. Powles and Hodson [108] use DeepMind’s case study teamwork with the Royal Free London NHS Foundation Trust to
address the need for transparency in how patient data is being shared with third parties. Regardless of the good impact on diagnosis/treatment of patients by the product
suite of Google, one of the significant issues addressed in the previous case study was a lack of patient consent. On the other hand, Sleep Apnea American Association, and
IBM [109] were collaborating to solve major healthcare challenges to examine sleep apnea (with IBM’s Watson supercomputer at home) in thousands of Americans, with in‐
formed and clear patient consent. That was critical to implementing the national standard for interoperability in the healthcare system of IT. Which was emphasized by
Wachter and Hafter through a white paper in UK NHS in comparison to the US healthcare sector that emphasized the significance of interoperability in permitting patient
Electronic Health Records (EHRs) over various clinics, such as various trusts that do not maintain a separate system to get access on these records built by different vendors.

Fig 7

Sharing health information using BCT.

In a report of Harland Simon on a project justifying RFID tagging in NHS Cambridge shire, about 15% loss of assets annually, resulting in a substantial cost to repurchase the
items that hospitals previously have. Furthermore, as per GE Healthcare [110] report, nurses spend an average of 21 minutes per shift searching for misplaced devices as
stated by, defining any device under $5000 as consumable and to again purchase if any device is lost, suggesting significant cost in the sector. Published by Harland Simon, an‐
other study reported that [111], by adopting radio frequency identification (RFID) standards for tracking of medical devices, NHS Forth Valley in Scotland had saved nearly
£400,000 in cost avoidance by not having to buy the important devices which would have been lost by the medical system. Tracking of Drugs has been a completely different
issue than tracking of devices because a major concern is counterfeits of drugs here. According to WHO’s report, In the US up to 10% supply of Pharmaceutical products is
counterfeit. In the United States, the Food and Drug Administration (FDA) recently approved the utilizing the RFID to track pharmaceuticals between the supply side to the
patient. It enables the whole sequence kept supervised, to make sure that pharmaceuticals were purchased from a legitimate source. Pfizer was the first pharmaceutical com‐
pany to use RFID “e-pedigree” to ensure that patients and doctors could trust the source and capabilities of their flagship medicine, Viagra, after identifying it as one of their
most counterfeited drugs. Because of the use of low-cost passive RFID tags and barcodes, the system enabled the pharmacists and wholesalers to check the authenticity of
their Viagra through a simple RFID scanner at a low rate than Pfizer.
3) Records of patients Blockchain is having the potential to significantly disrupt health services and place data in the patient’s hand. The specific intriguing steps are in
MedRec [86], which provides doctors and patients with an immutable log of a health record as shown in Fig 8. That has a different approach to incentivize miners by provid‐
ing access to anonymized data about health in exchange for network maintenance. MedRec maps Patient-Provider Relationships (PPRs) using Smart Contracts when the con‐
tract displays a reference list having relationships between nodes on the Blockchain-system. This too places PPRs in the patient’s hand, empowering them in accepting, reject‐
ing, or modifying relations with health service providers for example doctors, insurers, and hospitals, etc. Blockchain-system allows for interoperability in the health system
by providing a decentralized ledger of accepted facts in healthcare records to which all health service providers are having access. It implies that while user interfaces may
differ, the central ledger would be the same across all service suppliers. A challenge that exists relates to the current state of health records across providers, which contain
significant amounts of the same information under different identifiers that may not be linked. This causes replication, and as the blockchain system increases in size, it is re‐
duced in performance. The level of data duplication in all records will necessitate replication to maintain a reasonably performant system with unique, anonymized identifiers
to identify the patient in all kinds of service. Adopting the blockchain health record is a business challenge in and of itself. The important thing is that medical records will not
start from zero because they would have to replace the current setup, and that is challenging. Furthermore, the sheer volume of data generated in the healthcare sector is
ever-growing, with Kaiser Permanente estimated to have between 26 and 44 petabytes of data on its 9 million members from EHRs and other medical data in 2014. The data
volume which is logged and referenced would mainly exacerbate the scalability issue.

Fig 8

Records of patients.

4) Drug tracking Another opportunity is tracking the drugs using a blockchain system as shown in Fig 9, which takes advantage of its immutability in the development of
tracking and a chain of custody from manufacturer to patient. Chronicled is a technology startup company that is working on its product, Discover, that develops a chain of
custody model that shows the manufacturing place of a drug, the places it had been since then, and when it was disbursed to patients, hence reducing the pharmaceutical
theft and fraud. That enables the health professionals in meeting existing standards of the pharmaceutical supply chain, along with focusing on interoperability among health‐
care professionals. The Counterfeit Medicines Project has been launched by Hyperledger, the Open-Source Blockchain Working Group, to address the issue of counterfeits of
medicines. The origins of counterfeit medicines would have been tracked and thus eliminated from the chain of supply. One benefit of tracking drugs by blockchain-system
over conventional methods is the inherent decentralization of trust and authority in the technology’s principles; whereas chief authorities could have bribed or faked, it is
much more difficult to bribe a consensus of those on the blockchain. As a result, an existing standard in pharmaceuticals tracking in industry, ePedigree, which already em‐
ploys RFID and a traditional database, is transitioning to its blockchain application. If medicines/drugs could be tracked and developed at the point of manufacture using
blockchain’s inherent anti-tampering capabilities, that will remove the counterfeited pharma products engaging in the supply chain.
 Fig 9

Drug tracking.

5) Device tracking Tracking of medical devices is one aspect of Block chain in disrupting healthcare, from manufacturing to decommissioning. The monetary benefit gener‐
ated through tracking of assets is clear; NHS East Kent Hospital discovered 98 infusion pumps they had no idea they still owned across three sites as concluded through the
case study of Harland Simon [111] in which active RFID trackers were implanted. Because of this single case study, they saved $147,000 at $1,500 per person. The use of
blockchain in conjunction with this technology allows for an immutable ledger that not only shows the current location of the device, also the location of the lifecycle, along
with the serial number, distributors, and the manufacturer linked with the device, assisting with regulatory compliance. Deloitte identified the competency among the poten‐
tial game-changers for blockchain in the domain of healthcare in a white paper. According to an IBM study, 60 percent of government stakeholders in healthcare believed the
integration of medical devices and asset management as the most likely area of disturbance in industry. The blockchain-based system has various advantages above conven‐
tional products of location tracking. This immutability and tamper-proof properties of the Blockchain are the most obvious. This prevents a malicious user from changing or
deleting a device’s location history. This is especially important given that theft of devices and shrinkage has been a major issue in the United States and the United Kingdom.
This immutability, in addition to preventing traditional theft, also protect devices from being lost and reordered, that have incurred high cost in terms of both actual equip‐
ment cost and care provided. The setup must not add significantly to the workload of staff, nurses, or workers because that requires tapping the device only using a mobile
phone and further entering the device location. Whereas the use of blockchain on the Internet of Things (IoT) is still in its early stages, Huh states a method to communicate
the devices using an Ethereum blockchain and public key system of RSA. Likewise, the device while it stores on blockchain its public key also stores the associated private key
on the device.

Discussion

This study aimed to conduct an organized analysis of previous literature about the employment blockchain in healthcare for a better understanding of their current and
probable state. The four key research problems are defined for this reason. RQ1 was presented with summing up top writers, publishers, publication houses, and designs of
publication patterns of this subject. Furthermore, it included an existing outline of research about employing blockchain in the healthcare space. The comprehensive descrip‐
tion of the reviewed articles is discussed in Table 3. RQ2 was designed to help researchers better understand how blockchain can be used, it is responded by defining particu‐
lar themes and sub-themes that reflect key aspects in employing blockchain in this sector. RQ3 further discussed its shortcomings and obstacles that previous researchers
had encountered. We were able to recognize the research gap in the existing literature and responded to this question by summarizing its main research themes and existing
limitations. RQ4 concentrated on the key aspects where future investigation can provide valuable insight. The fourth research question is addressed by combining findings
through emerging differences, shortcomings, and previously proposed guidelines.
 Table 3

Comprehensive description of reviewed studies.

Ref Methods Description Channel Proposed / Components

Implemented

[45] Public blockchain Details about the algorithm are provided. multi-tier, public Implemented PBEDA, ECDH, MVP, and ECDSA

[46] MAM is used for real-time broadcasting Algorithm details are provided. IOTA Implemented Masked Authenticated Messaging for Tangle,
activity via wearable’s Merkle hash technique, Merkle signature
scheme, One-time signature

[47] Computing Edge There was little information available on the The channel was Proposed WSN and Wireless sensor network controller
outcomes and efficiency. Ethereum v.2, computing Edge

[48] Not Available MedRec was used to do a cost analysis, but no The channel was Proposed Ethereum Go-client, QuorumChain algorithm,
algorithm or data were given. Ethereum classification, smart contracts, cipher manager,
proxy re-encryption

[49] UID system Details about the algorithm are not provided. Ethereum channel Proposed UID system, analytics of Big Data, history &
registration contract

[50] Not Available Details of the algorithm are provided, along The channel was Proposed Internet of Things, Merkle tree, Diffie–Hellman
with security margins that have been verified Bitcoin key exchange, and digital ring signature
against defined criteria.

[51] Not Available Details about the algorithm are provided. The channel was Implemented Practical Byzantine fault tolerance consensus
Consortium mechanism,

[52] PSO Performance results from a static study based N/A Implemented ADB, boosting for ML, reverse engineering,
on specific assessment criteria feature selection & extraction

[53] Not Available Details about the algorithm are not provided. Federated blockchain Proposed IoT sensors WBANs, oracle
no experiments.

[54] Proposed signature scheme based on Attribute Details of mathematical and computational Not Available Implemented Diffie-Hellman computational bilinear, MA-ABS
notations given for execution of scheme, scheme
performance, and security evaluation

[55] With the support of a genetic algorithm In terms of input and output strings, block N/A Implemented Genetic algorithm, hash key cryptography, MD5
Proposed access control method based on creation, time processing, detailed simulation strings, discrete wavelet transforms.
blockchain results are provided.

[56] The proposed Blockchain-based eHealth The integrity-verification algorithm’s details Permissioned Implemented Byzantine Fault in Practice Algorithm for
Integrity Model uses a design-science and test results have been released. blockchain tolerant consensus
methodology.

[57] (HAR) Methods for recognizing human Some mathematical notations and N/A Implemented For HAR (ECOC) framework, (SVM), Multi-class
activity based on a uni model comprehensive findings for performance cooperative categorization technique, fog
reassessment studies on three datasets have computing
been given.

[33] Not Available For performance evaluation, precise N/A Implemented The Merkle tree with order-preserving
mathematical and algorithmic notations are encryption
supplied, as well as the outcomes of
experiments.

[59] Not Available The applicability of blockchain in healthcare is N/A Proposed Environment based on the blockchain
discussed using a concept-based approach.

[60] Preprocessing of images Details on the experimental results, Bitcoin Implemented HOG, LBP, SVM, RFT, DNN
classification training, and testing outcomes
were given.

[61] Pearson’s correlation, compression ratio The compression ratio and stability N/A Implemented (BAQALC) proposed, (NGS), (SRA), LZW
technique performance testing results were given. modification

[62] Methods of authentication Details on the algorithm and how it performs in Ethereum Implemented primitiveness verification (PV), preservation

Conceptual evolution

According to the findings of the study, research in healthcare’s blockchain was largely focused on enhancing more creating new ideas and concepts that help researchers to
derive multi-domain [59] also practicable blockchain in healthcare implementations. The viability of employment [99] is being established and evaluated across three sub-
themes of research: design creation, applications on benefit-based, and developing predictive competencies.
Concept development

The findings of the analysis indicate that new proofs and algorithms have received a lot of attention, such as proof of data primitiveness [62, 112], proof of familiarity [74],
and simpler workload for proof of work; [54]. Studies have also focused on testing new variables and components in architecture systems, as well as improving frameworks
that enable blockchain execution by including them. Consider cryptosystems based on attribute [72], approach the Stackelberg game [63], sibling intractable functions [70],
and homomorphic computations for more efficient frameworks [77]. Further [113], suggested a new scheme (BBDS) based on blockchain to protect data transactions and
maintain privacy [57]. Used fog computing estimation efficiency as well as reliable models for human pursuit acknowledgment to support remote e-health controlling [51]. To
eliminate a single point of failure, they are focused on incorporating several time sources into their technique. Finally, this research has centered on how to boost the effi‐
ciency of already established algorithms and structures based on the blockchain.

Benefit-based application

Blockchain has been used in healthcare research to extract concrete benefits by identifying and testing new technology avenues. It involves work in upgrading the technical
advantages of employing blockchains, such as advanced image processing [60], effective behavior recognition [57], and Internet-of-Things synchronization (IoT) devices [51].
Furthermore, the majority of studies in this category have centered on the use of blockchain technology to establish specific benefits of healthcare, e.g. mutual decision mak‐
ing in the medical field [74]. Blockchain adoption, for example, is being suggested to have positive implications while managing clinical trials [73], DNA data transmission [61],
preventive healthcare, biomarker growth, and discovery of drugs are all examples of remote patient monitoring [50, 53, 64].

Advancing decentralization

Existing research is also considering promoting key advantages of blockchain technology throughout healthcare environments for encouraging justice and also efficient de‐
centralization [76, 114]. For instance [63], produced an efficient framework for promoting maximization of revenue maximization along with fair decentralized trade, consid‐
ering that [48] stated the need for trade-offs for mining benefits. Researchers in previous literature already described blockchain’s prospects in developing transparency in
exchanging the data [56], such as utilizing upright client roles [21, 30]. By doing this, we can say that previous research about the increasing use of blockchain-based technol‐
ogy in the medical space is focused on spreading decentralization along with its related advantages.

Advancement in technology

Current studies have contributed substantial progress in terms of advancement and refinement of blockchain for the development of targeted deployment, particularly in the
healthcare space. We suggested previous research that is classified in this theme be directed regarding the three main topical issues based on our review:

Developing intelligent healthcare ecosystems

The introduction of blockchain technology programs into healthcare environments has piqued the interest of some academics [45]. Such integrations can pave the way for
the development of intelligent healthcare systems [100]. For example [47], argues that blockchain adoption will aid in the development of a more efficient e-health ecosystem.
Prior research has also suggested frameworks for developing blockchain-based e-health [56] and telemedical information systems [33], which could help healthcare
providers, expand the scope of their services in the future.

Improvements to the blockchain architecture on a technical level

The majority of this field’s study has concentrated on improving the efficiency of architectures and developed systems by technological improvements for example utilizing
smaller data block sizes [74] and reducing transaction propagation delay [68, 74]. Some attention has also been given to problems that have previously been described as
possible roadblocks to the successful implementation of blockchain architectures. Memory and CPU specifications [77], as well as accurate node recognition, are among the
problems considered in research, grouped under this theme [71]. The efficacy of potential solutions to the above problems has been illustrated in several cases by network
and algorithm comparison studies [21, 30, 74]. However, we believe that this theme will continue to progress in the future, necessitating a parallel emphasis on comparative
analyses to determine the most powerful networks and algorithms.

Building predictive capabilities

A similar pattern can be seen in blockchain technology’s use in healthcare as it enters the fourth step in development with the rising integration of AI [26]. IoT [50], sensors
[47], wireless body area networks [53, 64], big data [49], edge computing [76], and cloud technology have all recently been incorporated through blockchain-based device
architecture [59]. Researchers are using such technologies to help them develop systems based on blockchain having predictive capacities for enhancing medical information
systems and diagnostics [61, 75]. Prescription fraud avoidance [47], verifiable data generation [77], and automatic claim resolution [47] have all been investigated previously
using such frameworks [72]. Furthermore, studies have centered on using blockchain-based technology in supporting providers of health care services with other tasks, e.g
data collection on population-level [46] and user identity description [28].

Enhancement of efficiency

Several researchers in previous literature have attempted to determine how blockchain-based implementation would improve the efficiency of healthcare processes [34, 59,
79, 82]. According to this study, scholars’ attention has been drawn to two facets of performance improvement: structures and processes.
Process

Prior research has focused on improving the efficiency of technological aspects of the processes that are needed to run a blockchain-based healthcare system. Prior research
has also focused on developing systems for timely alerts [72] and adverse event reporting [73]. Some research has centered on increasing the computational processes effi‐
ciency [57] and thorough evaluation of suggested architectures [60] to ensure that its architecture gives far efficient processing as compared to conventional architectures
[71]. Furthermore, studies have proposed changes in blockchain systems to resolve the alleged risks related to time management, data management, and managing related
costs. For example, reviewed research has established mechanisms for reducing the cost of implementation after setting up initially [74], lowering storage costs [65], and
making maintenance and storing files of any size is easier [62, 112].

System

According to our analysis of the current literature, several steps have been applied to enhance the blockchain-based healthcare framework holistically. For example, research
has focused on improving system interoperability [27, 49], managing inter-institutional access rights [63, 99], and data management [28, 46, 63, 64, 99]. Enhancing machine
scalability [113] and efficiency have also received scholarly attention [60, 65]. Researchers have concentrated their efforts on designing integrated service-oriented architec‐
tures [56] and enhancing the generalizability and flexibility of blockchain systems that have been implemented [21, 27, 30].

Management of data

According to the results, we can conclude that managing the data and medical records is getting more scholarly attention. Existing research has endorsed the blockchain’s uti‐
lization for medical data management [27, 48, 54, 55, 69, 70, 99, 115]. Furthermore, by integrating heterogeneous forms of data [27, 69, 100], blockchain can aid in the devel‐
opment of an application system of information to manage such PHRs [59, 64]. We define three main aspects of current research in this field based on the SLR.

Data privacy

Previous research about data security implications of this technology in medical care has focused on handling the privacy of data by maintaining permitted access to the data.
According to the study, access control management [76] has gotten a lot of attention [45, 46]. Because of the requirement of protecting the privacy of confidential data by
greater transparency, access control, and immutability, this problem is particularly important in healthcare [55]. Prior research has developed a framework based on
blockchain to guarantee the delivery of effective services [115], user-centric [114], and access to patient PHRs and other medical data that is safe and encrypted in response
to this vital need e.g. [45, 50, 54].

Data protection

Another main concern discussed in studies on the blockchain aspects of data management in healthcare is the avoidance of unauthorized access and the preservation of data
confidentiality to ensure data safety. The majority of the studies that were examined focused on preventing unauthorized access [66] and preventing eavesdropping [71].
Several methods have been proposed to achieve this aim, including efficient authentication [65], biometric authentication [49], user verification [55], and the use of dual sig‐
natures [63].

Data handling

Prior research has addressed the need for legally and legally compliant collection, sharing, and controlling of healthcare data to some extent. According to our findings, few
research studies have recognized the importance of monitoring enforcement [100], let alone the criteria and targets for compliance [63, 67, 75]. However, the importance of
data integrity has received a lot of attention [56, 69, 70]. Prior research has looked at issues like authentic data mobilization [46, 77], double storage expenditure [68], and
eternal data protection [68, 112, 116, 117]. Along with the growing inter-institutional adoption of blockchain, researchers have transformed their attention to the issue of
storing and maintaining sensitive data [67] from a variety of sources, including medical devices [52] and health insurance [77]. A few studies have concentrated on the assist‐
ance of cross-institutional sharing of data [67], as well as changes in data sharing quality and flexibility [69]. Additionally, previous studies have addressed the need for data
processing improvements (e.g. [77]). Some steps for inducing these changes have been suggested in the reviewed studies, such as the successful incorporation of diverse
data from various sources of data [99] and the integration of smart contracts [48]. These themes specify that past studies in that area have focused on (i) improving techno‐
logical features, (ii) managing medical databases, also (iii) identifying unique capabilities in the medical field, where blockchain could make remarkable contributions. Based
on emerging trends, it can be said that scholarship in this field is still transforming, with existing facets of healthcare being recognized as possible recipients of using
blockchain as a result of technological advancements.

Research framework for future synthesis

This analysis and review helped in the framework development which was created with the research gaps identified in existing recommendations suggested in previous re‐
search. The research model includes 5components that would aid in the development of the healthcare ecosystem based on blockchain, for future research. The research
framework for the BCT-based healthcare system is depicted in Fig 10.
 Fig 10

Research framework.

Data sources Personal and medical health records are created and managed by the patients using mobile devices, healthcare service suppliers, and pharmaceutics is one of
these associated industries., research and insurance [32, 47, 70]. These serve as the foundation of the blockchain architecture and need management by legitimate and regu‐
latory rules. This technology might aid in the development of authorized databases that information can be retrieved by inter-institutional authorities in collaboration with
the required agencies to aid in patient treatment and medical decision-making [21, 30]. Because of the incorporation of newer technologies, such as smart patient tracking
devices [53], to increase the comprehensiveness of medical databases, future research should concentrate on handling those data sources.

System architecture With advances in blockchain technology, the system’s architecture will undergo important changes and refinement in terms of the components incorpo‐
rated into the system of blockchain. Such as using Permissioned consortium blockchain [28] or platforms other than Ethereum [68, 77], could improve current blockchain de‐
ployment architectures in the healthcare ecosystem. Also, future research should concentrate on creating techniques for managing system architectures that have been estab‐
lished, particularly the challenging circumstances that can have an impact on the performance and efficiency, for instance, node management [74] and techniques of key dis‐
tribution [67].

Blockchain technology strategic implementation In the case of increasing integration of information and communication technology and blockchain over healthcare ecosys‐
tems, researchers should have focused on the elements which could impede and assist in the widespread application of blockchain technology. According to our findings, we
believe that organizations should think about whether or not, by identifying the key issues throughout this study, blockchain technology might prove a potential source of cre‐
ating or enhancing value. Strategic problems like resource constraints [50] and technical problems like performance uncertainty [56] and system requirements are these ex‐
amples [99]. Considering these problems might help scholars to develop blockchain architectures that can offer better functional utility and productivity in terms of resource
and output management. This can also guide health system administrators and personnel to adopt a holistic and strategic approach to the potential inclusion of blockchain as
an essential component of a company’s value chain.

Beneficiaries Databases built on the blockchain can provide trustworthy information to particular beneficiaries in the sector of healthcare, such as patients who keep owner‐
ship of their information. Authorities including doctors, pharmacists, medical researchers, and insurance firms are also beneficiaries. Patients may authorize them to use
medical information for a range of purposes, plus collaborative medical decision-making [63], medical informatics and diagnosis (S.J. [61]), and fraud prevention [47].
Because of the blurring of the borders between the health system, wellness sectors, and mobile phones, researchers must recognize such beneficiaries ensuring data is ac‐
cessed by the relevant authority. Moreover, the important thing is maintaining the integrity of data following ethical and legal bindings. As a result, scholars must concentrate
to understand the perspective of the user about the perceived advantages and costs of engaging in a blockchain system. It can assist to identify and remove obstacles in the
widespread application and use of blockchain.

Ethical & legal consideration Blockchain applications are addressing critical issues for example authentication, interoperability, and safe sharing of medical data [49, 118–
120]. Regardless of the increased emphasis on the blockchain, the acceptance of such concerns may be regarded as a remarkable barrier to its extensive adoption. More em‐
phasis should be placed on regulatory compliance [100] and ethical recommendation for issues like control of ownership and access of patient data [99]. We propose that
future scholars take a multidisciplinary approach to determine avenues for resolving ethical and legal compliance issues in multi-national or cross-institutional contexts for
blockchain adoption. We also argue that there is a need to positively impact the public and appease regulatory agencies by deliberating and highlighting the critical benefits
derived by using technology based on blockchain.

Directions for future research

According to the SLR, we provide a brief summarization of the thematic problems that would require attention from future researchers:

Deployment of holistic view In case it is critical to find solutions to security and performance-related problems, like interoperability [67] and access-control [68], we argue
that scholars must take a broader view of blockchain adoption. This is critical to creating holistic, legally, and ethically compliant [21, 30], robust data management, and au‐
thentication procedures in e-health ecosystems [33]. Furthermore [36], argues that context variables like people and culture may play an important role in the development
of new technologies. Eventually, we suggest testing blockchain-based electronic health ecosystems in cross-institutional and cross-national contexts to build tailored context-
based healthcare solutions in collaborating with different organizations inside the healthcare space, such as research medical centers [60].
Optimization of the architecture Scholars might focus on improving the efficiency and performance of proposed designs to account for the higher transaction rates which
may be expected if blockchain is integrated into healthcare operations in the future [113]. That can be accomplished by dealing with network congestion [69], scalability [99],
throughput [76], and bandwidth issues [22].

Data protection & legal compliance Addressing data, plus user privacy and legal problems will be an important area of future research [21, 30, 53]. These can be directly tack‐
led by designing blockchain protocols in handling healthcare records that can be enforceable by smart-contract [36] and compliant with data and privacy protection regula‐
tions, for example, Health Insurance Portability and Accountability Act [31, 36, 53].

Other technologies integration For improved functionality, deployment of block-chain might be advantageous by the technology with business processes in healthcare [36].
For example, researchers can concentrate to advance the incorporation of edge computing, AI, and ML through blockchain health service ecosystems in developing an im‐
proved anticipatory analytic model to provide customized health treatment and diagnostics (e.g. [52, 63, 64]). Furthermore, research may aim to improve accessibility, remote
control, and emergency services via the integration of sensors based on IoT. Furthermore, we propose two additional potential directions for future scholars to extend the
existing scope of academic boundaries in this sector. First of all, it proposes the requirement to understand the implications of blockchain deployment in more niches in
healthcare, but related fields i.e. managing the digital rights of users’ [13], drug prescription management [11], and prescription fraud prevention [47]. Furthermore, the re‐
search could be conducted to investigate the implications of blockchain usage across the whole health system supply and value chain. It can help scholars better understand
user-related interoperability problems and additionally enables creating standard protocols to use systems working under the blockchain.

Conclusion

This research study is designed to understand completely the application of blockchain in the domain of healthcare. To achieve this goal, SLRs were conducted on nine highly
regarded databases using particular protocols to pick out relevant articles for review. The outcomes were used, to sum up, current knowledge on applications of blockchain
in the specific sector of medical care, but to also summarize past and the present academic research theme trends in this field. Future research possibilities have been show‐
cased in the form of a synthesized framework created by combining insights from existing restrictions, suggestions, and emerging gaps in current knowledge observed
throughout this review.

Supporting information

S1 Checklist

PRISMA 2020 checklist.

(DOCX)

Click here for additional data file.(31K, docx)

Funding Statement

The author(s) received no specific funding for this work.

Data Availability

All relevant data are within the manuscript and its Supporting information files.

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Published online 2022 Apr 11. doi: 10.1371/journal.pone.0266462.r001

Decision Letter 0
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Additional Editor Comments:

Based on the comments of the reviewers, I recommend minor revision for this paper.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously,
with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please
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on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors
should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publi‐
cation, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: irst of all, I congratulate all of the authors for working on the significant topic of blockchain technology in health care. I have a few suggestions listed below:

In table 3, write a complete name instead of writing single alphabets.

Correct the sequence of Figure 6. (i.e. Security and Privacy).

Reviewer #2: In this work, the authors have done a survey on Blockchain Technology in Healthcare. The study is compiled by reviewing research articles published in nine
well-reputed venues such as IEEE Xplore, ACM Digital Library, Springs Link, Scopus, Taylor & Francis, Science Direct, PsycINFO, Ovid Medline, and MDPI between January
2016to August 2021. A total of 1,192 research studies were identified out of which 51 articles were selected based on inclusion criteria for this SLR that presents the modern
information on the recent implications and gaps in the use of BCT for enhancing the healthcare procedures. A framework is developed to address the probable field where
future researchers can add considerable value, such as data protection, system architecture, and regulatory compliance. Hence, The paper can be accepted after making the
following Minor corrections.

1. There are few grammatical errors in the manuscript. So English proof reading is required. For example, “The research studies of [13] and [14] have been discussed” could
be written as “The research studies of [13] and [14] have discussed”.

2. I don’t find X-Axis and Y-axis values in “Figure 3”.

3. Some important recent references are missing, the following references must be totally added in the Section "References" (otherwise, the reference is not enough, then it
must be revised again until it is enough):

The Application of the Blockchain Technology in Voting Systems: A Review

Homechain: A blockchain-based secure mutual authentication system for smart homes

Human-in-the-loop-aided privacy-preserving scheme for smart healthcare

Profile Matching for IoMT: A Verifiable Private Set Intersection Scheme

**********

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Reviewer #1: No

Reviewer #2: No

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2022; 17(4): e0266462.
Published online 2022 Apr 11. doi: 10.1371/journal.pone.0266462.r002

Author response to Decision Letter 0

12 Feb 2022

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are referring to the actual images within the Figure, rather than the Figure as a whole).

Author response: Thanks for the comment. We have revised the Figures, and all of the Figures are created by the authors of this paper. In addition, Figures 6,7,8,9, and 10 are
now Figure 5,6,7,8, and 9 in the updated manuscript.

2) Please state whether the images in Figures 6, 7, 8, 9, and 10 have been previously copyrighted.

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Please also clarify if you received explicit written permission from the copyright holders to publish the Cochrane Bias Tool in Figure 4 under CC BY 4.0.

Author response: Figure 4 is deleted from the updated manuscript.

2022; 17(4): e0266462.

Published online 2022 Apr 11. doi: 10.1371/journal.pone.0266462.r003

Decision Letter 1
Pandi Vijayakumar, Academic Editor

22 Mar 2022

Blockchain Technology in Healthcare: A Systematic Review

PONE-D-21-33056R1

Dear Dr. Malik,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all out‐
standing technical requirements.
Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript
will be scheduled for publication.

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Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Pandi Vijayakumar, Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Both the reviewers have given acceptance and hence the paper can be accepted for publication.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may
indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept"
recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously,
with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please
refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a
public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions
on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.
Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors
should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publi‐
cation, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: author addressed all the review comments satisfactory. Hence, I recommend the acceptance for this paper.

Reviewer #2: The authors have done all the corrections given in the previous round. So the paper can be accepted in the present form.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any at‐
tached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: MARIMUTHU KARUPPIAH

Reviewer #2: No
2022; 17(4): e0266462.
Published online 2022 Apr 11. doi: 10.1371/journal.pone.0266462.r004

Acceptance letter
Pandi Vijayakumar, Academic Editor

1 Apr 2022

PONE-D-21-33056R1

Blockchain Technology in Healthcare: A Systematic Review

Dear Dr. Malik:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production
department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materi‐
als, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For
more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.
Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Pandi Vijayakumar

Academic Editor

PLOS ONE